Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s associated with Alzheimer disease (AD) risk. We propose that these SNPs point to mechanisms that affect AD development and thus represent targets for AD drugs. More specifically, we propose that drugs that mimic the actions of the protective SNP allele represent potential ?genetically validated? pharmacologic agents. Notably, a SNP with modest molecular actions may impact disease modestly but a drug that acts strongly at the same target may impact disease robustly. While this has been accomplished in other diseases, the lack of GWAS translation to pharmacologic agents represents a key knowledge gap in AD. In this proposal, we will focus on rs35349669 (rs669), a common SNP within INPP5D that is strongly associated with AD. Collectively, our work on INPP5D, encoding the lipid phosphatase SHIP1, over the last 17 years has provided the framework for its role in neuro-immune modulation through a physical interaction with TREM2, another critical factor recently implicated in AD. Building on these discoveries, we have now developed SHIP1 small molecule inhibitors that are safe and effective in murine models, as well as SHIP1 conditionally deficient mice. New data from our group establish a direct mechanistic connection between SHIP1 and AD pathophysiology, by showing that INPP5D expression is increased with the rs669 allele associated with AD risk and with AD pathology. Overall, this study brings together an interdisciplinary team to critically test our global hypothesis: Pharmacologic or genetic inhibition of SHIP1 decreases AD risk or progression. For this effort, we propose the following Specific Aims: (i) Elucidate the mechanism underlying rs669, (ii) Elucidate SHIP1 molecular actions relative to AD pathogenic mechanisms, (iii) Define the optimal SHIP inhibition strategy to impact macrophage and microglial function in the CNS and (iv) Translate INPP5D genetics into a novel therapeutic agent. Overall, this focused proposal will develop our compelling molecular genetic results, elucidate the actions of SHIP1 in an AD context, and translate these changes into a possible AD-preventive agent.